Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires C1425ASU, Argentina; International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167), Buenos Aires, Argentina - Toulouse, France.
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
Cell Rep. 2020 Dec 29;33(13):108547. doi: 10.1016/j.celrep.2020.108547.
Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host, yet the responsible mechanisms remain elusive. Macrophage activation toward the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we ask whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We expose M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PEs) and find lower glycolytic activity, accompanied by elevated levels of OXPHOS and bacillary load, compared to controls. The eicosanoid fraction of TB-PE drives these metabolic alterations. HIF-1α stabilization reverts the effect of TB-PE by restoring M1 metabolism. Furthermore, Mtb-infected mice with stabilized HIF-1α display lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages (AMs). Collectively, we demonstrate that lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.
结核分枝杆菌 (Mtb) 通过调节巨噬细胞的代谢状态在宿主体内茁壮成长，但负责的机制仍难以捉摸。巨噬细胞向杀菌（M1）程序的激活依赖于 HIF-1α 介导的代谢从氧化磷酸化（OXPHOS）向糖酵解的转变。在这里，我们想知道结核（TB）微环境是否会改变 M1 巨噬细胞的代谢状态。我们将 M1 巨噬细胞暴露于结核性胸腔积液（TB-PE）的无细胞部分，与对照相比，发现糖酵解活性降低，同时 OXPHOS 和细菌负荷升高。TB-PE 的类二十烷酸部分驱动这些代谢改变。HIF-1α 稳定通过恢复 M1 代谢来逆转 TB-PE 的作用。此外，稳定 HIF-1α 的感染结核分枝杆菌的小鼠在肺泡巨噬细胞（AMs）中显示出较低的细菌负荷和明显的 M1 样代谢特征。总的来说，我们证明来自与 TB 相关的微环境的脂质通过阻碍 HIF-1α 功能来改变 M1 巨噬细胞的代谢重编程，从而损害对 Mtb 感染的控制。
